YAP suppresses gluconeogenic gene expression through PGC1α.

Area of Science:

• Cellular metabolism
• Molecular signaling
• Liver biology

Background:

• Cell growth and proliferation are intrinsically linked to cellular metabolism.
• Understanding the signaling molecules connecting these processes is crucial for development, regeneration, and cancer research.
• The transcriptional regulator Yes-associated protein 1 (YAP) is a known key regulator of liver size, development, and function.

Purpose of the Study:

• To investigate the role of YAP in regulating gluconeogenic gene expression.
• To elucidate the molecular mechanisms by which YAP influences metabolism.
• To determine the in vivo effects of YAP on glucose homeostasis and liver size.

Main Methods:

• Deletion and constitutive activation of YAP in primary hepatocytes.
• Assessment of gluconeogenic gene expression in response to hormonal stimuli (glucagon and dexamethasone).
• Investigation of YAP's interaction with peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1) and its effect on promoter activity.
• In vivo studies using constitutively active YAP to measure plasma glucose levels and liver size.

Main Results:

• Yap deletion potentiated the gluconeogenic gene response to glucagon and dexamethasone in primary hepatocytes.
• Constitutively active YAP suppressed gluconeogenic gene expression.
• YAP's effects were mediated by the transcriptional coactivator PGC-1, inhibiting its binding to and activation of gluconeogenic target promoters.
• Knockdown of YAP blunted these effects.
• In vivo, constitutively active YAP reduced plasma glucose levels and increased liver size.

Conclusions:

• YAP acts as a suppressor of gluconeogenic gene expression.
• YAP reprograms cellular metabolism, diverting substrates from gluconeogenesis towards anabolic growth processes.
• These findings highlight YAP's critical role in linking cellular metabolism to growth and maintaining glucose homeostasis.